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Gene that is crucial for antibody-producing cell development is key to blood cell cancer

28.08.2003

Finding that an abnormally active Bcl10 gene drives B cells to become cancerous suggests blocking the gene would be an effective treatment for MALT lymphoma

A gene that is crucial to the development and function of an entire family of immune cells is also key to understanding why one member of that family can become cancerous. Investigators at St. Jude Childrens Research Hospital and the Blood Research Institute at the Blood Center of Southeastern Wisconsin, Milwaukee, reported this finding in the September 2003 issue of Nature Immunology.

The St. Jude researchers had previously shown that one of these cell types, marginal-zone B cells, can give rise to a cancer called mucosa-associated lymphoid tissue (MALT) lymphoma when the cells abnormally over-express a gene called Bcl10. The current finding suggests that a drug that blocks the action of Bcl10 could be an effective treatment for this cancer.

The researchers discovered that Bcl10 activates a pathway of molecular signals that drives antibody-producing B cells to mature into one of three different members of this family of immune system cells: follicular, marginal zone and B1 B cells. Mice lacking Bcl10 have a significant decrease in mature B cells and cannot launch an effective antibody response against bacteria in their bloodstream.

To learn how Bcl10 controls B cell development and function, the investigators studied mice in which the gene was inactivated. The mice produced nearly normal numbers of immature B cells. However, these cells did not mature normally. This showed that Bcl10 function is essential for B-cell development.

The researchers found that mice lacking a functional Bcl10 gene could not activate specific pathways of signaling molecules that belong to a family of proteins called NF-êB. The NF-êB proteins are normally activated by Bcl10 after B cells encounter invading organisms, such as bacteria. These proteins then cause B cells to fully mature and release antibodies targeted against those specific organisms.

The central role of Bcl10 in B cell development and function is further evidence that this gene is a major contributor to the development of MALT lymphoma, according to St. Jude scientist Liquan Xue, Ph.D., the articles lead author.

"When Bcl10 jumps to a new location in a chromosome due to a genetic abnormality known as a rearrangement, it lands next to a section of DNA that forces the gene to be continually active," Xue said. "Bcl10 then continually activates the NF-êB proteins, driving the marginal-zone B cells to keep replicating themselves. That continual proliferation of the B cells leads to MALT lymphoma."

Demin Wang, an associate investigator at the Blood Research Institute, is the senior author of the article. He headed the work done at that location.

"Our discovery of the roles of Bcl10 in the development and functioning of B cells brings us a step closer to understanding how to control its activity and cure MALT lymphoma," Wang said. He is also an assistant professor at the Model Animal Research Center in Nanjing University, China, and at the Medical College of Wisconsin in Milwaukee.

The researchers also tested the ability of LPS, a molecule that forms part of the walls of some infectious bacteria, to stimulate marginal-zone B cells to multiply--a normal part of the bodys infection response. Located mainly in the spleen, marginal-zone B cells usually multiply after binding with the LPS in bacteria, increasing the numbers of B cells releasing antibodies. In mice lacking the Bcl10 gene, however, LPS failed to stimulate B cells to proliferate normally. This observation showed that the gene is required for this type of B cell to respond to infections.

Mice lacking Bcl10 genes were infected with a strongly disease-causing strain of Streptococcus pneumoniae, which causes one of the most common forms of pneumonia in humans. Unable to clear up the infection, these mice died. However, mice with normal Bcl10 genes mounted immune responses to the infection and survived.

"This study is an example of how basic research can hold the promise of tangible benefits to people suffering from a particular disease," said Stephan Morris, M.D., an associate member of the St. Jude Pathology and Hematology-Oncology departments and one of the articles authors. Morris, one of the discoverers of Bcl10, initiated the current studies and directed the work at St. Jude.

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Other authors of the study include Carlos Orihuela, Elaine Tuomanen, and Xiaoli Cui (St. Jude); and Renren Wen (Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee).

St. Jude Childrens Research Hospital St. Jude Childrens Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit http://www.stjude.org.

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